The convenience of administering a single dose of medication which releases active ingredient over an extended period of time as opposed to the administration of a number of single doses at regular intervals has long been recognized in the pharmaceutical art. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized. In most sustained release preparations known to the pharmaceutical art, medicinal agents are either coated with varying thicknesses of some type of relatively insoluble material or are imbedded into a rigid lattice of resinous material. In such preparations, the object is to continuously provide drug for absorption into the blood stream to replace the amount eliminated while the dosage form is passing through the gastrointestinal tract of the patient.
The conventional approaches to sustained release formulation briefly outlined above can be disadvantageous in that certain classes of active ingredients are not suited to absorption during passage through the gastrointestinal tract due to their physiochemical properties and/or favorable sites of absorption. For example, most acidic medicaments are principally absorbed from the stomach, whereas most basic medicaments are absorbed primarily from the intestines. Most medicaments will undergo varying degrees of change in solubility by passage from the acutely acidic conditions of the stomach to the neutral to alkaline conditions of the intestines. For example, ferrous salts are more soluble in the stomach than in the intestines. Finally, there are medicaments, e.g., antacids, which are intended to act in the stomach and therefore lose most beneficial properties when they pass into the intestines.
It is readily apparent in view of the above considerations that a large number of medicaments are not amendable to conventional sustained release formulations which are not retained in the stomach and which release medicament in the intestines. It is equally apparent that a sustained release formulation which is retained in the stomach and which slowly releases medicament in the stomach over an extended period of time would be eminently suited to such medicaments. Such a sustained release formulation is provided by the present invention.
The principle of sustained release which characterizes the tablets of the subject invention is unique in the art, i.e., the tablets remain buoyant and free floating in the gastric fluid for an extended period of time, during which substantially all of the medicament is released therefrom. Although many mechanisms of sustained release are recognized in the art and the concept of a floating tablet is recognized, there is no teaching which recognizes the application of buoyancy to sustained release as is taught by the subject invention.
For example, Davis U.S. Pat. No. 3,418,999 teaches a tablet which is buoyant. However, the buoyancy of the tablet is disclosed as being merely an adjunct to swallowing and there is no suggestion therein of applying the buoyancy to sustained release. The Davis tablets also must have an initial density of less than 1, whereas the tablets of the subject invention are not so restricted.
The concept of a tablet which swells when in contact with gastric fluid is also recognized in the art. For example, Johnson et al. U.S. Pat. No. 3,574,820 teach tablets which swell in contact with gastric fluids to a size such that they cannot pass the pylorus and therefore are retained in the stomach. It is readily apparent that such tablets are not buoyant since, if they were, their size in relation to being able to pass the pylorus would be of no consequence.
The incorporation of a swellable hydrocolloid in a sustained release tablet is also recognized in the art. Playfair U.S. Pat. No. 3,147,187 teaches incorporation of a swelling gum or proteinaceous material into a sustained release tablet to aid in disintegration of the tablet and thus expose more surface to digestion. There is no indication that the disclosed tablets are intended to be buoyant. This is further evidenced by the fact that all ingredients are combined into a melt which is thereafter cooled and granulated. The hydrocolloid is therefore formulated in the manner of a conventional tabletting binder as opposed to being added to the formulation in a dry particulate form as in the practice of the subject invention whereby it functions to facilitate the buoyancy of the tablet.
Finally, Christenson et al. U.S. Pat. No. 3,065,143 teach the use of a hydrocolloid in a sustained release tablet to form a water impermeable barrier on the outer surface of the tablet which gradually erodes and thus releases medicament over an extended period of time. There is no suggestion, however, that such phenomenon could be utilized to achieve a hydrodynamic balance for a tablet such that it will remain floating on the gastric fluid in the stomach for an extended period of time as in the subject invention.